Mediators of Pulmonary Vasodilatation in Liver Disease

描述(申请人提供)：肝肺综合征(HPS)是肝病的一种重要的血管并发症，15%-30%的肝硬变患者发生肺微血管扩张导致低氧血症。HPS的存在增加了死亡率，并且没有可用的药物治疗。胆总管结扎术(CBDL)诱导的实验性胆汁性肝硬变可复制人HPS的肺血管和气体交换异常。目前的周期显示，肝脏产生和释放内皮素-1(ET-1)以及肺组织内皮素B受体(ETB)表达增加是触发HPS的关键早期事件，eNOS通过产生NO来触发HPS。在肝前性门脉高压症中，肺组织ETB受体的表达也增加，但肝脏ET-1的产生不会增加，除非注入ET-1，否则HPS不会发生。肺ETB受体水平的升高与反映血管切应力增加的高动力循环的发展相关，而血管切应力是ETB受体表达的已知调节因素。随着CBDL后ET-1和ETB受体的改变，巨噬细胞也聚集在肺血管中，我们通过产生血红素加氧酶-1衍生的一氧化碳在稍后的时间点促进HPS的进展。ET-1和ETB受体介导的效应是否在肺内募集和激活巨噬细胞尚不清楚。初步研究表明，剪切力和ET-1参与了实验性HPS肺组织ETB受体的高表达，选择性抑制ETB受体可减少肺微血管eNOS，抑制肺血管内巨噬细胞聚集，改善HPS。我们的假设是，剪切力/细胞因子诱导的肺血管内皮细胞ETB受体过度表达介导了实验性HPS中内皮和巨噬细胞的ET-1效应。我们将1)明确肝硬变和门脉高压时肺血管内皮细胞ETB受体过度表达的细胞机制和后果，2)检测ET-1和ETB受体介导的作用是否有助于单核/巨噬细胞在肺血管内皮细胞的黏附和激活，3)评估ETB受体改变在实验性HPS发病机制中的作用。 公共卫生相关性：HPS是一种常见的临床问题，对肝硬变患者的生存有不利影响。我们研究的长期目标是利用对HPS中血管功能障碍的了解来开发药物治疗方法，并作为理解肝脏疾病其他血管并发症的发病机制的范例。

DESCRIPTION (provided by applicant): The hepatopulmonary syndrome (HPS) is an important vascular complication of liver disease where 15-30% of cirrhotic patients develop pulmonary microvascular dilatation causing hypoxemia. The presence of HPS increases mortality and no medical therapies are available. Experimental biliary cirrhosis induced by common bile duct ligation (CBDL) reproduces the pulmonary vascular and gas exchange abnormalities of human HPS. Current cycle shows that hepatic production and release of endothelin-1 (ET-1) and increased pulmonary expression of the endothelin B (ETB) receptor are critical early events that trigger HPS through eNOS derived NO production. Pulmonary ETB receptor expression is also increased in prehepatic portal hypertension but hepatic ET-1 production does not rise and HPS does not develop unless ET-1 is infused. Increased pulmonary ETB receptor levels correlate with the development of a hyperdynamic circulation reflecting increased vascular shear stress, a known modulator of ETB receptor expression. As ET-1 and ETB receptor alterations occur after CBDL, macrophages also accumulate in the pulmonary vasculature and we contributes to the progression of HPS at later time points, by producing heme oxygenase-1 derived carbon monoxide. Whether ET-1 and ETB receptor mediated effects recruit and activate macrophages in the lung is unknown. Preliminary studies support that shear stress and ET-1 contribute to pulmonary ETB receptor overexpression in experimental HPS and reveal that selective ETB receptor inhibition may decrease pulmonary microvascular eNOS, inhibit accumulation of pulmonary intravascular macrophage and improve HPS. Our hypothesis is that shear stress/cytokine induced pulmonary vascular endothelial ETB receptor overexpression mediates ET-1 effects in the endothelium and macrophages in experimental HPS. We will 1) define the cellular mechanisms and consequences of pulmonary vascular endothelial ETB receptor overexpression in cirrhosis and portal hypertension, 2) test if ET-1 and ETB receptor mediated effects contribute to adhesion and activation of monocytes/macrophages in the pulmonary vascular endothelium and 3) assess the role of ETB receptor alterations in the pathogenesis of experimental HPS in vivo. PUBLIC HEALTH RELEVANCE: HPS is a common clinical problem that adversely influences survival in patients with cirrhosis. The long-term goal of our studies is to use an understanding of vascular dysfunction in HPS to develop medical therapies and as a paradigm for understanding the pathogenesis of other vascular complications of liver disease.